The role of oxidative stress in menopause

Cardiovascular effects of menopause

Estrogen has been shown to play a physiologic role in the cardiovascular system by protecting against heart disease. This is facilitated via its atheroprotective effect on plaque stabilization and collateral vessel formation.[23,24] This hormone also has favorable effects on insulin, glucose, and lipoprotein levels in the serum.[24] However, because the antioxidant effect of estrogen is lost once women reach menopause, the incidence of atherosclerosis increases.[17] This is due to a variety of factors, one of which is a higher level of oxidized LDL in the blood.[21,24] Also, there is an overexpression of the angiotensin receptor, AT-I, in menopausal women, which contributes to the endothelial dysfunction and increased vasoconstriction seen in atherosclerosis.[25] Additionally, studies have shown that postmenopausal women have low levels (<1 μM) of nitric oxide, a natural vasodilator in the body. Such low levels have been shown to play a role in cardiovascular disease by allowing for more smooth muscle proliferation, inflammation, and atherogenic effects on the vasculature.[26,27] The higher levels of nitric oxide normally seen in premenopausal women provide cardioprotective effects and inhibit the propagation of smooth muscle typically seen in heart disease.[27] Furthermore, the marked reduction of estrogen during menopause increases free fatty acid levels. This makes postmenopausal women more susceptible to the metabolic syndrome and insulin resistance, both of which are implicated as risk factors for cardiovascular disease.[28] Thus, it is evident that the effects of declining estrogen and other substances during menopause can predispose women to cardiovascular disease.

Vasomotor disturbances

Oxidative stress is also involved in the pathogenesis of menopausal symptoms, such as vasomotor disturbances. These disturbances include hot flashes or night sweats. Hot flashes are defined as a sudden feeling of warmth usually over the face, neck, and chest. During a hot flash, the metabolic rate temporary increases, which often results in sweating, panic, and irritability.[29,30] Throughout menopause, there are repeated episodes of such vasomotor disturbances, which results in a prolonged increase of the metabolic rate. This increase has been show to contribute to the formation of oxidative stress by placing a hindrance on antioxidants and their function in neutralizing ROS.[29]

Osteoporosis

Osteoporosis is defined as a reduction in bone mineral density, which occurs when there is an imbalance between the creation of new bone and removal of old bone. A decline in estrogen has been shown to play a major role in this decreased bone mass during the onset of menopause, especially because it has a variety of protective effects on bone marrow and bone cells.[31,32] This can be seen via estrogen's significant impact on bone-resorbing osteoclasts, which are cells involved in the breakdown of organic bone and removal of mineralized matrix. In particular, this hormone allows for increased bone formation by reducing the production and function of these osteoclasts as well as increasing osteoclast apoptosis. This effect on the osteoclastic cells of the bone is facilitated via estrogen's inhibition of two signaling molecules, RANKL and CSF-1, which are involved in osteoclast differentiation and survival.[31,32,33,34] However, due to the estrogen deficiency during menopause, this beneficial effect on the bone is lost.

As stated earlier, the menopause induced hormonal deficit has been linked to an increase in inflammatory cytokines within the serum such as tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-10, and IL-12. These cytokines stimulate osteoclast and osteoblast formation, leading to increased bone turnover and eventually, bone loss.[22] Specifically, TNF-α, produced from macrophages and granulocytes, negatively impacts the bone by contributing to increased osteoclast formation. This occurs via direct stimulation of pro-osteoclastogenic activity of stromal cells.[22] Additionally, the high levels of FSH during menopause stimulate osteoclast differentiation and TNF-α production, both of which play an important role in osteoporotic bone loss.[35] Overall, it is evident from the role of pro-inflammatory cytokines and estrogen in bone remodeling that oxidative stress is a major contributor to bone density loss in osteoporosis.

Effects of oxidative stress on menopause

In healthy, premenopausal women there is usually an appropriate balance between free radical species and antioxidant mechanisms. As such, the level of oxidative stress in these women is not sufficient enough to affect the ovaries until the onset of menopause. In the aforementioned paragraphs, it has been stated that menopause creates a pro-oxidant state in the body due to the decline of the natural antioxidant, estrogen.[9,15] Consequently, the question often arises if oxidative stress can lead to menopause. The majority of studies have shown that oxidative stress alone in premenopausal women cannot induce menopause, but rather can lead to a variety of pathologies. Specifically, studies have reported that oxygen radicals have an important physiologic role within the ovary. However, the continuous synthesis of these harmful agents over time may lead to an increased cumulative risk of ovarian pathology. This includes premature ovarian failure, which is suggested to be exacerbated under conditions of reduced antioxidant status such as infection and autoimmune disease.[36]

Menopausal hormone therapy

MHT has been extensively researched as a potential treatment for the debilitating symptoms and sequelae of menopause. The aim of hormonal therapy is to enhance antioxidant defense mechanisms and decrease levels of oxidative stress in postmenopausal women.[37] A variety of researchers have found an association between MHT and its beneficial effect on oxidative stress. As such, most studies favor its administration to menopausal women. However, due to the fact estrogen has antioxidant and pro-oxidant characteristics, as well as a multitude of adverse side effects, some studies have not approved its use for the treatment of menopausal symptoms. A few studies even suggest that MHT has no significant effects on oxidative stress levels.[38,39]

Hormonal therapy has been shown to improve a variety of menopause-induced pathologies in the body, such as atherosclerotic heart disease. Specifically, the estrogen-progestin pill has been shown to reduce the risk of cardiovascular disease by opposing atherosclerosis. This is carried out via estrogen's downregulation of inflammatory markers such as chemokines and cell adhesion molecules.[24] Furthermore, it has been shown to potentially stabilize atherosclerotic plaques by reducing the expression of matrix metalloproteinases and the production of plasminogen activator inhibitor-1.[40] MHT also aids the cardiovascular system by downregulating both angiotensin receptor gene expression and smooth muscle proliferation. The former effect helps to lower blood pressure, while the latter aids in the prevention of atherogenesis. Additionally, the high concentrations of estrogen in MHT promote the dilation of vessels through the production of prostacyclin, inhibition of endothelin synthesis, and blockage of calcium channels.[40,41]

In addition to its advantageous effect on the cardiovascular system, hormonal therapy has been shown to have a similar effect on vasoactive biomarkers. For example, a study conducted on healthy postmenopausal women demonstrated that MHT given for 1 year significantly reduced levels of catecholamines, mean blood pressure, and LDL cholesterol while increasing levels of nitrite and nitrate. This suggests that MHT has a cardiovascular benefit in those who are menopausal.[38] Interestingly, it also showed that the amount of oxidative stress in the body was not greatly altered by 12 months of MHT usage. This was measured via the oxidative stress biomarker 8-epi PGF_2α, which did not significantly differ from its baseline value.[38] Other studies discussing the effect of hormonal therapy on oxidative stress showed decreases in serum lipid peroxides and upregulation of overall antioxidant status. Overall, it is clear that a definitive relationship exists between MHT and oxidative stress levels; however, the nature of this relationship cannot be confirmed.[42,43]

There are a considerable number of risks and side effects associated with MHT. These include increased risk of a pulmonary venous embolism, stroke, and cardiovascular events as well as a high incidence of estrogen-dependent breast, ovarian, and endometrial cancers.[39] It has been suggested that there is a certain window during the postmenopausal period in which MHT is most beneficial. Outside this time frame, estrogen intake can have detrimental effects on the body. The timing of MHT is crucial because the longer menopause continues, the greater the estrogen deficiency, which leads to a decreased activity of estrogen receptors. This reduced receptor activity, in turn, leads to severe endothelial dysfunction and eventually decreased vascular responsiveness as well as decreased effectiveness of MHT.[44]

Overall, current research indicates that postmenopausal women should use the lowest possible dose of MHT due to the aforementioned side effects.[45] However, long-term use of MHT may prevent cardiovascular disease if started in women at the onset of menopause. As such, the benefits of this pharmacotherapy seem to outweigh the risks for women under 60-year-old.[46]

Selective estrogen receptor modulators

SERMs are a class of compounds that act on the estrogen receptor, exhibiting agonistic actions of estrogen in some tissues and antagonistic actions in others. Two examples of SERMs are raloxifene and tamoxifen.[47] The former drug has antagonistic action in the uterus and breast, but agonistic action on the bone. Thus, the main use of raloxifene is to prevent and treat osteoporosis. Tamoxifen, however, acts as an agonist of estrogen receptors in the uterus but has antagonistic effects on the breast. Thus, its main use is to treat breast cancer. Similar to estrogen, raloxifene acts as an antioxidant due to the phenolic rings comprising its chemical structure.[47,48] Specifically, raloxifene's mechanism of action aims at decreasing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, an enzyme that produces free radical species. This is facilitated via the downregulation of rac1 protein, which is required for NAPH oxidase activation.[49]

Additional beneficial effects of this SERM includes an increase in superoxide dismutase levels, a free radical scavenger, an increase in nitric oxide release, and a compound that suppresses smooth muscle proliferation and atherogenesis. Furthermore, raloxifene improves the lipid profile by preventing macrophage lipid oxidation and it also decreases levels of pro-oxidant biomarkers with the blood, such as malonaldehyde.[49,50] Additionally, raloxifene may play a protective role in the cardiovascular system by improving endothelial function and decreasing blood pressure levels as demonstrated in a study conducted on hypertensive rats.[50] Overall, by targeting the estrogen-mediated pathways, harmful results of oxidative stress can be prevented in postmenopausal women.

Exercise

Exercise has been shown to modulate levels of oxidative stress within the body through a variety of mechanisms. Studies have reported transient increases in ROS concentrations following acute aerobic and anaerobic exercise. However, this increased oxidative stress may serve as a necessary signal for upregulation of antioxidant defense mechanisms and eventual reduction of free radical species.[50,51] Specifically, exercise training has been associated with reduced basal oxidant production and free radical leak during oxidative phosphorylation, both of which contribute to the high oxidative stress levels seen during menopause.[51] Moreover, physical activity has been shown to alleviate menopausal symptoms and sequelae, such as sweating, anxiety, depression, hot flashes, osteoporosis, and cardiovascular disease.[52,53] In particular, one study reported that postmenopausal women had higher levels of oxidative stress associated with increased fat content than women who were premenopausal. Therefore, exercise in this population is helpful to reduce body fat, which is highly beneficial in augmenting the antioxidant capacity of the body.[54,55] Overall, exercise has been proven to be a valuable, cost-effective option in alleviating menopausal symptoms and improving the redox balance in healthy, postmenopausal women.[7]

Vitamin C and E

Two dietary vitamins, vitamin C (ascorbic acid) and E (α-tocopherol), can be used to thwart the onset of various disorders associated with an age-related decrease in estrogen. Rich in their antioxidant capacity, these vitamins scavenge free radicals and neutralize oxidative stress.[58] One study assessing the effect of these vitamins on postmenopausal women found higher levels of the oxidative stress marker, malonaldehyde, and lower levels of the antioxidant enzymes, catalase and superoxide dismutase, in those who did not incorporate vitamin C and E in their diet.[59] These vitamins were not only helpful in achieving a favorable redox balance in the body, but they also are associated with a reduced risk of cardiovascular disease. This is mediated via their inhibition of cholesterol synthesis and LDL-cholesterol oxidation.[58,60]

In regards to the symptoms of menopause, both vitamins have been shown to reduce the intensity and number of hot flashes via promotion of adrenal function. This allows for increased hormonal production, specifically estrogen, allowing for a greater antioxidant defense system in postmenopausal women. When considering vitamin C alone, its intake has been associated with a protective effect on bone. This can be seen through its suppressive action on osteoblast and osteoclast activity, which thereby prevents accelerated bone turnover and eventual bone loss.[61,62]

However, at high doses, vitamin C and E have deleterious effects on the body. Specifically, large quantities of vitamin C (>2,000 mg/day) have been suggested to cause diarrhea, abdominal cramps, bloating, nausea, vomiting, and kidney stones.[61] While high doses of vitamin E (>1,000 mg/day) may increase the risk of bleeding by having an anticoagulant-like effect on the body and may also increase the risk of birth defects. Thus, when using vitamin C and E to quell the adverse effects of menopause, it is important that appropriate dosages be used.[56]